Thyrotropin-Secreting Pituitary Adenoma: a Structured Review of 535 Adult Cases

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C De Herdt and others Thyrotropin-stimulating 185:2 R65–R74 Review pituitary adenoma

ENDOCRINE TUMOURS Thyrotropin-secreting pituitary adenoma: a structured review of 535 adult cases

Carlien De Herdt1, Eva Philipse1,2 and Christophe De Block1,3

1Department of Endocrinology-Diabetology-Metabolism, Antwerp University Hospital, Antwerp, Belgium, Correspondence 2Department of Endocrinology-Diabetology, Heilig Hart Hospital Lier, Antwerp, Belgium, and 3University of Antwerp, should be addressed Faculty of Medicine and Health Sciences, Antwerp, Belgium to C De Block Email [email protected]

Abstract

Background and aims: Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare entity, occurring in one per million people. We performed a systematic review of 535 adult cases summarizing the clinical, biochemical, hormonal and radiological characteristics of TSHoma. Furthermore, we discussed the current guidelines for diagnosis and treatment. Methods: A structured research was conducted using Pubmed and Web of Science with the following MeSH terms: 'thyrotropin secreting pituitary adenoma' OR 'TSHoma' OR 'thyrotropinoma.' Results: Our analysis included 535 cases originating from 18 case series, 5 cohort studies and 91 case reports. The mean age at diagnosis was 46 years. At presentation, 75% had symptoms of hyperthyroidism, 55.5% presented with a goitre and 24.9% had visual field defects. The median TSH at diagnosis was 5.16 (3.20–7.43) mU/L with a mean FT4 of 41.5 ± 15.3 pmol/L. The majority (76.9%) of the TSHomas were macroadenoma. Plurihormonality was seen in 37.4% of the adenoma with a higher incidence in macroadenoma. Surgical resection of the adenoma was performed in 87.7% of patients of which 33.5% had residual pituitary adenoma. Post-operative treatment with a somatostatin analogue (SSA) European Journal of Endocrinology led to a stable disease in 81.3% of the cases with residual tumour. We noticed a significant correlation between the diameter of the adenoma and residual pituitary adenoma (r = 0.490, P < 0.001). However, in patients preoperatively treated with an SSA, this correlation was absent. Conclusion: TSHomas are a rare cause of hyperthyroidism and are frequently misdiagnosed. Based on our structured analysis of case series, cohort studies and case reports, we conclude that the majority of TSHomas are macroadenoma being diagnosed in the fifth to sixth decade of life and presenting with symptoms of hyperthyroidism. Plurihormonalitiy is observed in one-third of TSHomas. Treatment consists of neurosurgical resection and SSA in case of surgical failure.

European Journal of Endocrinology (2021) 185, R65–R74

Introduction

Hyperthyroidism is mainly due to autoimmune thyroid rarest form of pituitary adenoma accounting for 3% of all disorders, a toxic thyroid nodule or goitre and is rarely caused pituitary tumours and are frequently misdiagnosed, leading by a thyrotropin-secreting pituitary adenoma (TSHoma), a to an inappropriate treatment such as thyroidectomy (1, pituitary tumour characterized by an autonomous secretion 2, 3, 4). In 2013, the first European guidelines concerning of thyroid-stimulating hormone (TSH) (1). TSHomas are the the diagnosis and treatment of TSHomas were issued by

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hormones and TSH differthose ofadults. from andTSH hormones age under 16 years reference as their ranges of thyroid adenoma, ortreatment modalities, level diameter andfree ofthe T4(FT4),the ofTSH presence/absence ofgoitre, visualfield assessment, presentation, clinical age atdiagnosis, characteristics: following six of the missing more than eight TSHoma, than other diagnosis ). Exclusion criteria were). Exclusion criteria asfollows:

at the end of the article). article). endofthe at the C DeHerdtandothers ≥ 5cases) 1 , Figure 1 signs ofhyperthyroidism were present in75% ofpatients 45 wasage 46 atdiagnosis The female for to was male ratio 1.07. TSHoma The mean General characteristics Results distributed. normally lower whenand asmedianwith not andupper quartile were presented asmeanvalues measurements andlaboratory characteristics population two was used. StudySpearman’s variables, correlation and Q–Q plot. To investigate between a correlation tested for Kolmogorov–Smirnov by normality the test were data ofcontinuous Distributions characteristics. were statistics usedtoDescriptive analyse population pituitary adenoma Thyrotropin-stimulating ± 14 ( years case reports inthe

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s.d. Table 1 if normally distributed ifnormally 185 :2 ). Symptoms and R66 via freeaccess European Journal of Endocrinology hormone receptorantibodies. ACTH, adrenocorticotropichormone;AF,atrialfibrillation;FSH,follicle-stimulatingLH,luteinizingTRAbs,thyroid-stimulating † SSA monotherapy Radiotherapy SSA post-operatively SSA preoperatively Transsphenoidal resection (F) Treatment Co-secretion ofLH Co-secretion ofFSH Co-secretion ofACTH Co-secretion ofprolactin Co-secretion ofGH Plurihormonal (E) Co-secretion Ectopic tumour Diameter (mm) Macroadenoma (D) Adenoma TRAbs FT4 (pmol/L) TSH (C) Biochemicalpresentation Visual fielddefect Goitre AF and/orcardiacfailure Hyperthyroidism (B) Clinicalpresentation Age (years) Males (A) Demographics case. Immunohistostaining revealed majority the of that sinus sphenoidalis in 1 in 4 cases and in the nasopharynx 91 localizedinthe hadanectopic TSHoma, casereports respectively. andreports, caseseries mm inthe Five outof a mean diameterwith of 21.5 of3.75median TSH (2.16–25.3) mU/L. thyroidectomy andhada of TSHoma before diagnosis the 41.5 whereas FT4 averaged casereports the 35.7 and5.16 caseseries mU/L inthe (3.20–7.43) mU/Lin defects were in100 noticed (24.9%). patients failure wereheart seen in 11.1% cases. Visual of the field or of agoitrefibrillation Atrial was notassessed/reported. presence and 55.5%hadagoitre. cases,the Inhalfofthe Reported cases, if normallydistributedandasmedianwithlowerupperquartilewhennotdistributed. characteristics andlaboratorymeasurementsofthecaseseriescohortstudiesarepresentedasmeanvalues Table 1 Values presentedasmedian(lowerandupperquartile);*exclusionof(10)caseswhounderwentathyroidectomybeforediagnosisTSHoma. Review The majority (76.9%) were ofTSHomas macroadenoma was 6.75 atdiagnosis The medianTSH (4.02–11.90) ± † 15.3 pmol/L,respectively. Ten total casesunderwent (mU/L) Characteristics ofthepatientsattimediagnosisandtreatment.Themeanvaluesstudypopulation n

Case seriesandcohortstudies ± 7.9 mmand19.8 C DeHerdtandothers 6.75 (4.02–11.90) 21.5 35.7 143 (36.1) 396 (89.2) 140 (35.9) 334 (77.9) 109 (52.7) 302 (75.3) 219 (49.3) 74 (16.7) 56 (40.0) 78 (55.7) 86 (25.2) 62 25 (9.5) 46 444 ( 15.7) ± ± ± 7.9 8.5 6 ± 8.5and ± 13.6 Not reported 103 (23.2) 237 (53.4) 181 (40.8) 54 (12.2) 15 (3.4) 43 (9.7) prolactin levels.prolactin of FSHandLHwere Overproduction positive immunohistostaining for hadelevated prolactin GH hadacromegaly. Three outof16 adenomaswith positive23 adenomaswith immunohistostaining for Eleven hormone(s). co-secreted pituitary of the outof mixed adenomaresulted inoverproduction pituitary in microadenoma (27.3%). was more frequent inmacroadenoma (51.1%) than (ACTH). hormone Plurihormonality adrenocorticotropic adenoma, respectively. with No casehadco-secretion plurihormonal (LH) were in 26.5 and 8.8% of the reported (FSH) and luteinizing hormone hormone stimulating of follicle- co-secretion case reports, adenoma. In the was seenin41.4% prolactin with plurihormonal ofthe (GH) was seenin57.5% hormone growth andco-secretion adenomas (62.1%) were with Co-secretion pure TSHomas. pituitary adenoma Thyrotropin-stimulating 5.16 (3.20–7.43)* 41.5 Case reports 19.8 34 (49.3) 62 (78.5) 14 14 (15.9) 64 (73.6) 26 (32.5) 80 (87.9) 16 (47.1) 22 (64.7) 40 (44.0) 46 23(28.8) 45 9 (26.5) 5 (5.5) 4 (4.4) 8 (8.8) 7 (7.7) 3 (8.8)

( ± (23.3) 91 ± ± 63.9) 0 15.3* 13.6 14 Downloaded fromBioscientifica.com at10/02/202111:27:46PM Table 2 https://eje.bioscientifica.com Not reported 22 (24.2) 31 (34.1) 19 (20.9) 7 (7.7) 3 (3.3) 4 (4.4) 185 illustrates which :2 ±

s . d 174 (37.9) 396 100 (24.9) 155 (55.5) 366 (75.0) 169 (36.0) 469 (89.0) 100 (57.5) . 259 oras 81 (15.1) 85 (18.1) 72 39 (11.1) All data

535 (41.4) (76.9) (48.4) R67 n (%) via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com methimazole was started. Dueto was visualfielddefects, started. anMRI methimazole value IU/L, normal were (TRAbs) receptor positive antibodies hormone (15.28 of0.75high aTSH FT4with mU/L.Thyroid-stimulating and agoitre ( heat intolerance, tremor fibrillation, presented atrial with disease ( had concomitant Graves’ TSHoma Four with patients Concomitant Graves’disease adenoma. pituitary in age orsex vs between with residual without those was absent.There were correlation no differences this SSA, 0.001). However, preoperatively inpatients treated with adenoma( adenoma andresidual pituitary betweenthe the diameter of a significantcorrelation failure. a goitre fibrillation/heart We didobserve oratrial presence of adenomaorthe diameter ofthe andthe TSH 15.1% ofcases. gammastereotactic was in knife performed radiosurgery 12 months). intwo outoffivesurgery time to relapse cases(medianwas ( had a relapse. The median follow-upreports was 11 time of12time ( of which 13 amedianfollow-up hadastable diseasewith cases, 16 20 these were post-operatively treated SSA with cases were operated had residual of whichdisease. Of 20 werereports evaluated 91 Of the in detail. 80 case reports, operated case cases.Theof the ofthe treatment modalities tumourwas Residual present in33.5% pituitary function. thyroid the to analogue(SSA) normalize a somatostatin of caseswhich 36%were preoperatively treated with gonadotrophins. positive adenomaswith immunostaining forthree the seen inrespectively oneoutofnineand ACTH, adrenocorticotropichormone;FSH,follicle-stimulatingLH,luteinizinghormone. LH FSH ACTH Prolactin Growth hormone Hormone of thecasereports. Table 2 5 – Review 24 We between level found the nocorrelation ofFT4or Treatment therapy including radiation pituitary with Transsphenoidal was in89% performed resection ) months. Relapse occurred within the first the Relapse within year after occurred ) months. 5 Overview oftheresultsimmunohistochemicalexaminationadenomavsbiochemicaloverproduction.Analysis , 6 , 4 5 7 , – ). Laboratory tests). Laboratory revealed anunmeasurable 8 16 ). The first case was a55-year-old man who ) months. Five) months. outof80operated case < 2).Graves’ and diseasewas diagnosed, Immunohistostaining C DeHerdtandothers 16 22 3 9 0 r

= 0.490, P

hyperthyroidism andagoitre ( 55-year-old symptoms classical woman with of presenting was a The was restarted. secondpatient and methimazole no residual tumour. were TRAbs elevated still (5.62IU/L), (0.22mU/L)was seen.Thesuppressed MRIshowed TSH operatively, anelevated amildly FT4(36.36pmol/L)with staining was positive Oneyear for andprolactin. post- TSH The adenomawas resected andimmunohistochemical was revealing performed pituitary of the amacroadenoma. was pre-treated with an SSA after which the adenomawaswas pre-treated after anSSA which the with revealed pituitary MRI ofthe amacroadenoma. The patient test showedstimulation animpaired An response ofTSH. of5.4mU/L.TRH pmol/L) andanon-suppressed TSH an elevated with recurred FT4(48.3 Hyperthyroidism thyroidectomy was performed. andapartial diagnosed, showed a diffusely increased uptake. Graves’ disease was mU/L) andpositive (14 TRAbs IU/L).Radionuclide scan an elevated FT4 (37.6 (1.8 TSH a normal pmol/L) with hyperthyroidism andagoitre ( was a36-year-oldpatient woman symptoms with of immunohistostaining was positive for The fourth TSH. impaired The adenoma was response resected ofTSH. and test showed (TRH)stimulation releasing hormone an repeated showing adenoma. Thyroid- enlargement of the relapsed The andanMRIwaswas headache started. IU/L). Graves’ andmethimazole diseasewas diagnosed, of0.27mU/L.suppressed TSH were TRAbs positive (5.0 revealed anelevated only FT4(29.6pmol/L)with amildly had nosymptoms tests ofhyperthyroidism. Laboratory which revealedheadache amicroadenoma ( a 40-year-old woman who anMRIbecauseofa underwent was patient The was third started. IU/L), andmethimazole of0.765TSH remained mildly mU/L.TRAbs elevated (6.11 elevated (30.72 aninappropriately normal pmol/L)with hyperthyroidism didnotimprove, andFT4remained positive for Post-operatively, TSH. symptoms the of adenoma was resected and was immunohistochemically MRIrevealedIU/L). The pituitary amacroadenoma. The (0.337 TSH normal were mU/L). TRAbs positive (5.63 an elevated FT4(51.07 aninappropriately pmol/L)with pituitary adenoma Thyrotropin-stimulating Biochemical overproduction 11 1 1 0 3 Downloaded fromBioscientifica.com at10/02/202111:27:46PM 8 6 ). Laboratory tests). Laboratory revealed ). Laboratory tests). Laboratory showed 185 :2 Not reported 7 ). The patient ). The patient 0 4 0 4 6 R68 via freeaccess European Journal of Endocrinology potassium iodide. Immunohistochemically the adenoma iodide. Immunohistochemicallypotassium the being intubated. Shewas treated hydrocortisone with and developed afever, hypertension andtachycardia while still patient was Immediately performed. the thereafter macroadenoma. Transsphenoidal adenoma of the resection of9.19TSH revealed pituitary mU/L.AnMRIofthe a testsLaboratory showed anFT4of89.8pmol/Landa longstanding symptomswith of hyperthyroidism ( werewhich SSAs started. again andaresidual tumourwas MRIfor shown onthe Twelve weeks post-operatively levels thyroid hormone rose was notmeasured. Post-operative thyroid levels normalized. immunohistostaining for andGH. The level TSH ofIGF-1 tumour revealed positivethe adenoma with a pituitary and dexamethasone. Histopathologicalexamination of was treated propylthiouracil, with revealed ahighly elevated FT4of87.5 pmol/L.The patient Thyroid arguments of infection. testwithout function hadafeverpatient andconfused andbecamelethargic and hypertension. Immediately post-operatively, the developed patient surgicalprocedure, the tachycardiathe craniotomyfrontal tumour. debulking of the with During right mU/L. FT4was underwent notmeasured. The patient level TSH patient’s day the was before 6.4 operation, the tumourwas immediatelysuspected, andthe resected. The brain revealedof the was a large mass. Craniopharyngioma signs of hyperthyroidism ( without headache was an first patient 18-year-old a with manpresenting or post-operativelyperi- have been published ( Two complicated casesofTSHoma athyroid storm with Thyroid storm a follicular thyroid carcinoma of15 mm( of lymph metastases in two cases ( diameter ranging between 12 presence and 40 mm and the thyroida carcinoma with hadapapillary Eight patients carcinoma was ( years ofTSHoma before diagnosis the or agoitre, except forthyroid findingof onecasewhere the contextultrasound inthe performed ofhyperthyroidism 11 Nine outof91 hadathyroid carcinoma ( casereports Thyroid cancer 18 throughout normal years offollow-up. for Post-operative TSH. test thyroid remained function showedresected. Immunohistochemistry positive staining Review , 12 The secondcasewas a 54-year-old woman presenting , 13 , 14 ). In all patients, the carcinoma was found the on ). Inallpatients, C DeHerdtandothers 12 β , -adrenergic blockade -adrenergic blockade 15 ). One patient had ). One patient 15 ). 16 16 ). The MRI , 17 ). The 9 , 15 17 10 ). ). , case series, mean age at diagnosis was meanage 46 atdiagnosis case series, decadeoflife andsixth ( fifth the our analysis) ( between men and women (female of to1.07 male ratio in are equally TSHomas distributed of thyroid function. assays TSH immunometric measurement and routine ofultrasensitive awareness, introduction practitioner the which isprobably duetobeen described, anincreased 3 adenoma( 0.5–3%ofallpituitary and representing inoneamillionpeople are rare,TSHomas occurring Discussion levels.hormone year post-operatively thyroid the which normalized remained elevatedhormones were andSSAs one started Thyroidwas was positive normal. for andGH.IGF-1 TSH overproduction, calledbiologicalsilent adenoma,as doesnotalwaysPlurihormonality translate into hormonal by thyrotrophic asPit-1. andlactotrophic cells,such factors expressionby ofcommontranscription the or galactorrhoea, respectively ( (41.4%), possibly leadingto acromegaly andamenorrhoea ( hormone and37.9%TSHomas pituitary co-secreted anterior another ( isnotclear pathogenesis 1) gene hasbeendemonstrated, butits exact role inthe factor 1(Pit- positive pituitary-specific transcription of the favouring Overexpressionmutation tumourprogression. a gain ofproliferative followed function by asecondary after might atransforming arise TSHoma event providing commonly inhumancancerhave activated beenidentified. inoncogenes No inorigin. mutations are monoclonal adenomatous unknown. are transformation still TSHomas involvedThe molecular mechanisms in thyrotrope Pathogenesis andplurihormonality studied cases. led to treatment aswas inappropriate seenin11% ofthe thyroid diseasethat another or were with misdiagnosed past, ofhyperthyroidism many hadalonghistory patients probablythe the age differsofonset from ofdisease.In often delayedof the age atdiagnosis ofTSHoma, diagnosis pituitary adenoma Thyrotropin-stimulating , 4 ). In the last three decades,anincreased last incidencehas three ). Inthe These mixed adenomas can be explained pituitary In ouranalysis, 62.1% adenomaswere of the pure 9 , 10 2 ). Age of diagnosis is variable butismostly in isvariable ). Age ofdiagnosis ), most frequently GH(57.5%) andprolactin Downloaded fromBioscientifica.com at10/02/202111:27:46PM 1 , 2 ). 1 , https://eje.bioscientifica.com 1 3 , ). 2 ). Inouranalysis ofthe 185 ± :2 6years. Because R69 1 , via freeaccess 2 , European Journal of Endocrinology https://eje.bioscientifica.com the measurement ofglycoproteinthe alpha-subunit hormone The central first with is step inapatient hyperthyroidism ( approach European Thyroid proposed adiagnostic Association infour ( been reported casereports ( level TSH their despite doseofL-thyroxine increasing the or received radioactive iodineandare unableto normalize who athyroidectomyconsidered underwent inpatients subacute autoimmune ( thyroiditis (e.g. oestrogens), pregnancy, non-thyroidal illnessand asinterference such fromof conditions medication levelsthyroid hormone which may beseeninavariety exclude assay interference in changes andtransitory hyperthyroidism testing to isto repeat laboratory The first centralpatient. step indiagnosing orelevatedinappropriately normal inahyperthyroid level TSH isconsidered whenA TSHoma the is Diagnosis population. particular ultrasound in this frequent may to useof the TSHoma beattributed with ( per 100 per year persons general 000 in the population of thyroid carcinoma, ascompared to anincidenceof17.6 literature 9outof91 search, hadadiagnosis casereports TSHoma. Inour thyroid with finding of cancerinpatients disease ( unilateral to andbilateral Graves’ exophthalmos secondary invasion andhasto from bedistinguished TSHoma by the exophthalmos inafew isreported casesdueto orbital field defects in were24.9% ofcases. noticed Unilateral temporal visualfielddefects ( symptomsare present with oflocalcompression including which explains why ofdiagnosis time 30–40%ofpatients in 11.1% ofcases( were fibrillation found failure and toatrial be present heart hyperthyroidism. A goitre was present in 55.5%. Thyrotoxic 75% ofcases,are often mildincomparison to primary Symptoms andsignsofhyperthyroidism, present in Clinical features reported. hasbeen hypercortisolism with mixed TSHoma pituitary also shown inouranalysis ( 18 4 Review ). The coexistence ofGraves’ has diseaseandTSHoma ). The higher prevalence ofthyroid cancerinpatients Diagnosing a TSHoma is challenging. In2013, ischallenging. aTSHoma Diagnosing the The majority are large andinvasive ofTSHomas atthe 2 ). Acontroversial concomitant subject isthe 1 ). A diagnostic flowchart isshown in ). Adiagnostic 2 , 3 ). 2 3 , ). Until now). Until nocaseofa 3 , C DeHerdtandothers 4 ). Inouranalysis, visual 5 2 , ). A TSHoma must be). ATSHoma 6 , 7 , 8 ). Fig. 2 . been reported ( been reported So far, only fiveTSHoma inadultshave casesofan ectopic gene ispresent in85%.Acomparison between TSHoma thyroid- inthe RTH.Amutation with inpatients normal relativesphenotype infirst-degree ( thyroid character,clue isasimilar biochemical first the autosomal dominant Becauseofthe to thyroid hormones. receptor leadingto reduced responsiveness oftarget tissues inthe mutation RTHisanautosomal dominantinherited in TSHoma. tests thyroid from are those function indistinguishable as indicative for isnolonger recommended ( aTSHoma than one Therefore, cut-offofmore useofasingleratio the higher inpostmenopausal ratio women incontrast to men. levels ofLHand FSH into account.This leadsto amuch cut-off to suggestratio the circulating TSHoma musttake a the lesslikely diagnosis butdoesnotexcludethe past, it. Inthe inmacroadenoma ( in particular, ( of the normal population, including patients with RTH( with patients including population, normal of the findingin and canbeseenas an incidental a TSHoma 10% The finding ofamicroadenoma isnotspecificor TSH. for levelbetween adenomaandthe diameter ofthe ofFT4 the anelevated with serum highly suggestive ifassociated for particularly aTSHoma, hyperthyroidism is with of amacroadenoma inapatient diameter of21.5 76.9% to amean bemacroadenoma with ofTSHoma ( structures surrounding the The majority are macroadenoma invading ofTSHomas presence ofdynamictesting suggestivethe for TSHoma. ( diagnosis aboutthe uncertainty T3 suppression test is,therefore, is only usedifthere induce tachycardia failure ( andinsomeheart cardiovascular with and in those disease because it can and specific butis contraindicated in elderly patients This dynamic test most sensitive isconsidered the (100%) TSHoma. T3administration inallsubjects with to the day 8–10 during days. isnotsuppressed inresponse TSH isgiven patient adoseof80to 100the ( TSHoma subjects with administration of200 level RTH,TSH with increases afterand inpatients i.v. liothyronine (T3) suppression test. In healthy controls test anda aTRHstimulation Dynamic testing includes in and RTHissummarized pituitary adenoma Thyrotropin-stimulating α -GSU), which iselevated inabout70% TSHoma, ofthe α An MRI of the pituitary isonly recommended in pituitary An MRIofthe To dynamictesting isadvised. TSHoma, diagnose In patients with resistance (RTH), to with thyroid hormone In patients -GSU to TSH ratio was However, determined. ratio -GSU to TSH using the 19 ± , 7.9 The presence caseseries. mminthe 20 β -isoform of the thyroid hormone thyroid hormone -isoform ofthe , 21 μ 3 , Downloaded fromBioscientifica.com at10/02/202111:27:46PM g TRHbutnotinupto 85% of α 22 ). With T3suppression test, the -GSU. We found nocorrelation Table 3 , 23 3 , ). 4 4 1 . ). Ouranalysis showed ). ). A normal level). Anormal makes 3 ). The serum ). The serum 185 μ :2 g liothyronine a 1 , α -GSU is 4 ). The R70 3 , 3 4 via freeaccess ). ). β

European Journal of Endocrinology SSTR 2and5( receptornumber ofsomatostatin (SSTR), particularly ACTH andGH.Most thyrotrophic cells express avariable FT4 levels, age orsex. or to TSH adenoma, butnotinrelation diameter ofthe the 4 to a worse be associatedreported with surgical outcome ( intra- andperitumoural fibrosis. Tumour invasion hasbeen tends to have a higher of microscopic invasion degree and ( TSHoma with inupto 80%ofpatients thyroid function caneffectively largest surgery restorethe publishedseries, analysedwas in89%ofthe performed cases.According to adenoma as ofthe istranssphenoidal resection of choice ( experience andclinical case series in2013Association andupdated in2019 are basedon Treatment European guidelinespublished by Thyroid the Treatment 3 ). We to outcome a worse in relation clinical also describe Review ). In comparison to other pituitary adenomas, TSHoma adenomas,TSHoma pituitary ). Incomparison to other SSAs haveTSH, SSAs of the secretion effects on inhibitory 4 ). Incaseofsurgicalfailure, SSAs C DeHerdtandothers 1 , 2 , 3 ). The treatment 2 , authors haveauthors suggested recently may SSA play that arole didnot become euthyroid SSA beforewith Some operation. ( does not alwaysSSA lead to a euthyroid stage before surgery thyroid storm post-operatively ( evidence-based. We found two caseswho suffered from a preoperatively isto prevent is not a thyroid storm but this reason suggested adenoma.Another toof the give SSA alinkbetweennot observe diameter outcome andthe in subjects preoperatively we treated SSA, with could a higherwith rate ofremission ( because preoperative euthyroid status was notassociated since somestudies improved didnotobserve outcomes and now isnoconsensus reducing tumoursize,butuntil there preoperativelyof SSA couldimprove surgicaloutcome by aprevalencewith between 10 and30%.Administration areSSA hyperglycaemia, all andcholelithiasis, diarrhoea oftreatment. Sideeffects of first 3months the within and reduce tumour size in 30 to 50% of adenoma patients have in90%of secretion beenfound TSH to normalize pituitary adenoma Thyrotropin-stimulating 25 ). In our analysis, pre-treated 6 out of 26 case reports Diagnostic flowchart. Figure 2 Downloaded fromBioscientifica.com at10/02/202111:27:46PM 16 https://eje.bioscientifica.com , 17 2 ). Pre-treatment with ). Pre-treatment with 185 , 24 :2 ). Importantly, R71 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com increases back to normal levels to normal increases back after several ormay months first and second the week post-operatively)gradually and immediate post-operativethe alowest phase(with level After isundetectable complete in TSH tumourresection, Follow-up ( surgery of refusal ofpituitary analysis, thyroidectomy total one case underwent because hyperthyroidism which is very rare in TSHoma ( hyperthyroidism which rare isvery inTSHoma suffers from life-threateningnot curative patient andthe radioiodine is are only indicated surgery when pituitary less used. much panhypopituitarism, therapy iscurrently radiation availabilityresult ofthe risk of the of effective and SSA ( TSHoma residual orrecurrent with in patients therapy was was contraindicated usedwhen surgery or administration. of duration therapy andto the determine asprimary SSA role of the Studies secretion. are neededtoTSH objectify of inmonotherapytreated SSA hadnormalization with ( ( surgery hypopituitarism between and15 4months years after 131 including series 21 patients, subjects (16%) developed ofpost-operative risk hypopituitarismthe ( therapy reducing as primary treatment of TSHoma in the M, males;F,females; *Less vsprimaryhyperthyroidism;**riseofTSHto5–30mU/Lafter20min;***TSH Treatment MRI pituitary DNA mutationanalysis T3 suppressiontest TRH stimulationtest Dynamic testing TSH Biochemical Age atdiagnosis Sex Incidence Epidemiology Goitre Atrial fibrillation Visual fielddefect Positive familialhistory Anamnesis/clinical examination hormones (RTH). Table 3 7 α – Review 15 -GSU Total thyroidectomy with or thyroid ablation Before the introduction of SSA, pituitary radiation radiation pituitary of SSA, Before introduction the ) months, seven) months, eight analysed outofthe casereports 26 Comparison betweenthecharacteristicsofthyrotropin-secretingpituitaryadenoma(TSHoma)andresistancetothyroid , 27 , 28 α -GSU, glycoproteinhormonealpha-subunit; , 29 ). During a mean follow-up). During of 12 time 30 ). C DeHerdtandothers Surgery Macro- (80%)/micro-adenoma Negative TSH unsuppressed TSH mostlystable(85%) ↑ ↑ Mostly 40–50years M 1–2/million Mostly yes(70%) Mostly not* 30–40% No TSHoma = F 24 ). In4case 3 ). Inour 2 ). Asa ↑ , increase; ↓ and women, mostly at their fifth and sixth decade. andsixth Three- and women, fifth mostly attheir review equally occurred of535 inmen cases,TSHoma rare isavery cause ofhyperthyroidism. InourTSHoma Conclusion or visualfielddefects occur ( test andearlier levelsfunction ifthyroid hormone increase recommended every 2–3years regardless ofthyroid year andonceyearly thereafter. imagingis Pituitary first post-operative inthe times three evaluate patient the guidelinessuggestcurrent to andbiochemically clinically first infrequent ( inthe year after successfulsurgery are accurate needed to Recurrence obtain seemsto data. be but nofollow-up was available for 36cases.Larger studies analysis, only relapsed 5outof80operated casereports median follow-up of7years (range 1–21) ( ofKirkman series ( complete removal adenomaisaT3suppression test ofthe test ( orT3suppression response to TRHstimulation normal levelshormone evaluate while others remission by a focus andthyroid onTSH remission. Someauthors required. now, Until isnodefinition for biochemical there ( resection levelTSH oneweek isindicative ofcomplete after surgery lowoccasionally ( remain permanently , decrease;=,withinthereferencerange. pituitary adenoma Thyrotropin-stimulating 1 ). Recurrence has been reported in up to 30% of the case inupto 30%ofthe ). Recurrence hasbeenreported < 1mU/L;****mutationinthethyroid- 2 ). The most sensitive andspecific test to document 1 ). Transient levothyroxine replacement is t al. et andvan Varsseveld Downloaded fromBioscientifica.com at10/02/202111:27:46PM L-thyroxine ifnecessary Microadenoma ispossible positive in85%**** TSH TSH = ↑ Mostly atchildhood M 1/40 000 Mostly yes(80%) Mostly not* No Yes RTH 1 = ). F ↓ ↑ *** ** β gene. 185 2 ). Anundetectable :2 31 t al. et , 32 ). Inour with a with 1 ). The R72 via freeaccess European Journal of Endocrinology References integrity ofthedataandaccuracyanalysis. C D H and C D B are guarantors of this work and take responsibility for the manuscript. the edited and data the discussed authors All figures/tables. made and manuscript the of draft first the wrote H D C manuscript. the of content and search literature of process the discussed B D C and P E H, D C data. the analyzed and search literature the performed P E and H D C Author contributionstatement public, commercial,ornot-for-profitsector. This work did not receive any specific grant from any funding agency in the Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest EJE-21-0162. at paper the of version online the to linked is This Supplementary materials tumour. residual pituitary and the TSHoma diameter of the the outcomes ( invasion to leadto has been reported poorsurgical adjunctive orwithout with therapy. SSA resection Tumour The for istranssphenoidal treatment ofchoice TSHoma T3 suppression test, followed pituitary. by anMRIofthe test ora aTRHstimulation either includes of aTSHoma The diagnosis therapy ofpatients. aswas seeninone-tenth canleadto inappropriate Misdiagnosis is challenging. aTSHoma ofthyroid carcinoma. Diagnosing diagnosis isaconcomitant Inrare cases,there GH andprolactin. alsohavepatients overproduction, mostly of hormonal in macroadenoma. However, only ofthese one-quarter is more frequently seen macroadenoma. Plurihormonality were Most TSHomas ofpatients. in one-quarter 55.5% have agoitre andvisualfielddefects are present signs ofhyperthyroidism, are present with quarters 4 3 2 1 Review Tjornstrand A &Nystrom HF. disease: ofendocrine Diagnosis Beck-Peccoz P, Giavoli C &Lania A.A2019 update onTSH-secreting Amlashi FG &Tritos NA. Thyrotropin-secreting adenomas: pituitary Beck-Peccoz P, Chatterjee K Lania A,Beckers A, &Wemeau JL. 2013 diagnostic approach to TSH-producing pituitary adenoma. pituitary to TSH-producing approach diagnostic 1401–1406. adenomas. pituitary 427–440. epidemiology, andmanagement. diagnosis, Journal tumors. treatment ofthyrotropin-secreting pituitary European Thyroid and guidelinesfor diagnosis Association the 2013 2013 (https://doi.org/10.1007/s12020-016-0863-3) 2 (https://doi.org/10.1007/s40618-019-01066-x) ). We alinkbetween first to report are the 2 76–82. Journal of Endocrinological InvestigationJournal ofEndocrinological (https://doi.org/10.1159/000351007) C DeHerdtandothers Endocrine https://doi.org/10.1530/ European Thyroid 2016 2016 2019 2019 European 52

pituitary adenoma Thyrotropin-stimulating 12 10 18 15 13 17 16 14 11 8 6 9 7 5 Olson E, Wintheiser G,Olson E, Wolfe KM, Droessler J &Silberstein PT. Kishida M, Otsuka F, Yokota K, Kataoka H, Oishi T, Yamauchi T, Unluturk U, Sriphrapradang C, Erdogan MF, Emral R, Guldiken S, d’Herbomez M,Kamoun M, Lemaire C, Fayard A, Desailloud R, Arai N, Inaba M, Ichijyo T, Kagami H &Mine Y. Thyrotropin-producing Fu J, Wu A, Wang X Graves’ &Guan H.Concurrent disease Li J, Tan H, Huang J, Luo D, Tang Y, Yu R of &Huang H.Casereport Fujio S, Habu M,Yamahata H, Ashari, Moinuddin FM,Bohara M, Page KA, Roehmholdt BF, Jablonski M &Mayerson AB. Development Perticone F, Pigliaru F, & Deiana L,Furlani L, Mortini P Mariotti S, Inoue H, Shinojima N, Ueda R,Yamamoto K, Igata M, Ishii N, Gasparoni P, Rubello D, Persani L &Beck-Peccoz P. Unusual association Kiatpanabhikul P, Chantra K, Navicharern P, Shuangshoti S, Poggi M, Pascucci C Monti S, &Toscano V. Arare caseoffollicular org/10.1210/jc.2012-4142) andMetabolism Clinical Endocrinology offouradenomas: areport casesandreview literature. ofthe presence ofresistance and TSH-secreting toin the thyroid hormone Refetoff S &Gullu S.Management ofdifferentiated thyroid cancer org/10.1159/000355386) European Thyroid Journal adenomaandgraves’ pituitary hormone-secreting hyperthyroidism. Huglo D &Wemeau JL. Coexistence ofthyroid-stimulating org/10.1186/s13256-016-1172-4) case report. Graves’ adenomasimultaneously existing with pituitary disease:a fendo.2020.00523) Frontiers inEndocrinology thyrotropin levels: andreview literature. acasereport ofthe suppressed adenomapresenting pituitary secreting and TSH org/10.1097/MD.0000000000011047) Graves’adenoma with disease. thyrotropin-secreting induced by pituitary fibrillation atrial recurrent EJE-16-1029) Journal ofEndocrinology Epidemiology of thyroid cancer: a review of the National Cancer areview ofthyroid cancer: National Epidemiology ofthe 1131–1136. adenoma:acasereport. pituitary secreting Nishijima YArimura H, Thyroid &Arita K. storm inducedby TSH- org/10.4158/EP.14.6.732) adenoma. pituitary ofathyrotropin-secretingof thyroid storm after surgicalresection org/10.1089/thy.2014.0222) from alarge consecutive series. cases ofthree thyrotropin-secreting adenomas?Report with patients thyroid incidenceofdifferentiated cancerincreased in Losa M. Isthe org/10.1016/j.wneu.2018.07.274) hyperthyroidism. visualdisturbance with thyroid carcinoma presenting without papillary adenomacoexisting with thyrotropin-secreting pituitary Kawashima J, Iwase H, Mikami Y Araki E, thy.1998.8.181) thyroid carcinoma. between adenomaandapapillary athyrotropin-secreting pituitary (https://doi.org/10.1507/endocrj.47.731) adenocarcinoma. thyroid papillary adenomacoexisting with pituitary TSH-producing with a patient Doihara H, Tamiya T, Mimura Y, Ogura T jocn.2017.02.050) of ClinicalNeuroscience andmanagement.carcinoma: inpathogenesis challenges thyroid tumorandpapillary pituitary of TSH/GH-secreting Kingpetch K, Houngngam N &Snabboon T. Acaseofcoexistence (https://doi.org/10.1097/MAJ.0b013e3181949948) adenoma. thyrotropin-secreting pituitary with thyroid carcinoma inapatient American Journal of the MedicalSciences Journal ofthe American (https://doi.org/10.1507/endocrj.ej14-0278) Journal ofMedicalCaseReports World Neurosurgery Thyroid Endocrine Practice Endocrine 2017 2017 2017 2017 2014 2014 2020 1998 Downloaded fromBioscientifica.com at10/02/202111:27:46PM 41 177 3 11 78–80. Medicine Thyroid 60–64. 60–64. R183–R197. 8 523. 181–183. Endocrine Journal Endocrine 2018 2018 https://eje.bioscientifica.com 2013 2013 2008 2008 (https://doi.org/10.1016/j. 2015 2015 (https://doi.org/10.3389/ 2018 2018 (https://doi. et al. et al. 2017 2017 119 98 Endocrine Journal Endocrine 14 185 (https://doi.org/10.1089/ 25 (https://doi.org/10.1530/ 97 2210–2217. Hyperthyroidism in Hyperthyroidism 732–737. Arare caseof 394–399. 11 417–424. e11047. :2 2009 2009 9. 2000 (https://doi. 337 (https://doi. (https://doi. (https://doi. (https://doi. (https://doi. Journal 47 462–465. 2014 2014 Journal of 731–738. R73 61 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com

20 25 23 22 24 21 19 Review Macchia E, Gasperi M, Lombardi M, Morselli L, Pinchera A, Acerbi G, Pinchera A, Lombardi M, Morselli L, Gasperi M, Macchia E, Cossu G, Daniel RT, Berhouma M, Pierzchala K, Pitteloud N, Lamine F, Usui T, Izawa S, Sano T, Tagami T, Nagata D, Shimatsu A,Takahashi JA Koriyama N, Nakazaki M &Hashiguchi H, Aso K,Ikeda Y, Kimura T, Cooper DS &Wenig BM. causedby Hyperthyroidism anectopic Foppiani L, DelMonte P, Ruelle A, Bandelloni R,Quilici P& Nagai K, Wu CC, Sakata S, Wada H, Yokoyama K, Takada M, Kashiwai T org/10.1007/BF03346535) InvestigationJournal ofEndocrinological adenomas:asinglecenter experience. thyrotropin-secreting pituitary outcome in andtherapeutic Clinicalaspects Rossi G &Martino E. 018-0921-3) management. systematic review andmeta-analysis ofpostoperative outcomes and Colao A &Messerer M. Thyrotropin-secreting adenomas:a pituitary org/10.1007/s11102-005-3759-4) microadenoma. pituitary Clinicalandmolecularfeatures ofaTSH-secreting & Naruse M. eje.0.1510587) Endocrinology Graves’adenoma associated with disease. Eto H, Hirano H, Nakano S, Tei C. Thyrotropin-producing pituitary org/10.1507/endocrj1954.39.413) report. & Tokimitsu N. Thyrotropin-secreting adenoma:acase pituitary org/10.1089/thy.1996.6.337) tumor. pituitary TSH-secreting Investigation andbiologicalfeatures. clinical multifaceted with tumors Bernasconi D. adenomas:rare pituitary TSH-secreting cureus.4127) 2000–2013.Database, Endocrinologia Japonica Endocrinologia 2007 2007 2004 2004 Pituitary 30 151 603–609. Cureus 2019 2019 587–594. Pituitary 22 2019 2019 1992 (https://doi.org/10.1007/BF03346356) 79–88. Thyroid (https://doi.org/10.1530/ 2005 2005 11 39 e4127. 2009 2009 413–419. C DeHerdtandothers 1996 (https://doi.org/10.1007/s11102- 8 127–134. European Journal of 32 (https://doi.org/10.7759/ 6 Journal of Endocrinological Journal ofEndocrinological 337–343. 773–779. (https://doi. (https://doi. (https://doi. (https://doi. Accepted 15June2021 Revised versionreceived4June2021 Received 16March2021

pituitary adenoma Thyrotropin-stimulating 30 29 28 26 32 27 31 Kirkman MA, Jaunmuktane Z, Brandner S, Khan AA,Powell M Daousi C, Foy PM &MacFarlane IA. Ablative thyroid treatment for Teramoto ASanno N, &Osamura RY. surgicaloutcome in Long-term Gatto F, Grasso LF, Cuny T, Nazzari E, Anania P, DiSomma C,Colao A, Yamada S, Yamaguchi-Okada M, Horiguchi K, Fukuhara N, Rotermund R, Burkhardt T, Riedel N, Matschke J, Schmidt NO, van Varsseveld NC, Pereira AM, Biermasz NR, Bisschop PH, Fliers E expressing pituitary adenomas: presenting symptoms, adenomas:presenting expressing pituitary treatment, & Baldeweg SE. hormone- Active andsilentthyroid-stimulating (https://doi.org/10.1136/jnnp.2006.095661) Journal ofNeurology, Neurosurgery, andPsychiatry thyrotoxicosis dueto tumours. thyrotropin-producing pituitary 2000 16 adenoma. thyrotropin with pituitary patients s11102-014-0611-8) therapy?first-line might analogshave somatostatin adenomapatients: secreting arole as of high rate ofTSH- post-surgical hypopituitarism anterior inacohort Zona G, Weryha G, Pivonello R org/10.3171/2014.7.JNS1471) 90 cases. adenomas: asingle-center studythyrotropin-secreting of pituitary outcomes in andtherapeutic characteristics Clinicopathological Takeshita A,Nishioka H, Takeuchi Y, Ito J &Inoshita N. doi.org/10.1007/s00701-017-3105-4) adenomas. pituitary Aberle J &Flitsch J. Surgicaltreatment andoutcome ofTSH-producing 2014 2014 adenomas. thyrotrophin-secreting pituitary follow-up& Drent ML. Along-term study ofeighteen with patients (https://doi.org/10.1016/j.wneu.2014.03.031) outcomes, andrecurrence. 80 93 395–402. 194–200. Journal ofNeurosurgery (https://doi.org/10.1111/cen.12290) Pituitary (https://doi.org/10.3171/jns.2000.93.2.0194) Acta Neurochirurgica 2015 2015 World Neurosurgery Downloaded fromBioscientifica.com at10/02/202111:27:46PM 2014 2014 et al. 18 583–591. Clinicaloutcome andevidence 121 2017 2017 1462–1473. 185 Clinical Endocrinology (https://doi.org/10.1007/ 2014 2014 159 2007 2007 :2 Journal ofNeurosurgery 1219–1226. 82 (https://doi. 78 1224–1231. 93–95. (https:// R74 via freeaccess